Caries, or tooth decay, is the consequence between an imbalance between demineralization of enamel due to production of organic acids by bacteria of the plaque biofilm, and remineralization from saliva. Caries has an extremely high morbidity, with 60-90% of children and nearly 100% of adults worldwide having had caries, ac- cording to the WHO. As the most prevalent chronic disease, caries is an important public health problem and contributes significantly to the exorbitant dental expenditure - about $110 billion/year in the US alone. There is, therefore, a clear and present need for innovating caries prevention, early detection, and minimally invasive restoration. A major bottleneck is our lack of understanding of the etiology of enamel caries at the nanoscale. This is a consequence of the difficulties encountered in characterizing structure and chemistry of enamel, a complex hierarchical nanocomposite with significant heterogeneity in structure and composition. Herein we show that atom probe tomography (APT), a chemical imaging tool with unrivaled spatial resolution (<0.4 nm) and unbiased chemical selectivity, is uniquely able to deliver quantitative structural and compositional information at the required resolution. Specifically, we discovered the presence magnesium-rich amorphous inter- granular phase (AIGP) that is also enriched in carbonate, and residual organic matter. We further show that this AIGP is preferentially dissolved in acid and provides a short circuit diffusion path for fluoride. Based on this preliminary data, we hypothesize that the Mg-rich AIGP plays an integral role in enamel de- and remineralization and the development of caries lesions. A major goal of this application is to quantitatively compare the distribution and composition of the AIGP in pristine outer enamel and the surface zone enamel of carious sub surface lesions. We will do so by carrying out analyses of enamel on human teeth extracted for orthodontic rea- sons, using both APT and correlative techniques. A second goal is to establish an in vivo rat model for the development of caries lesions in the PI's lab for future longitudinal studies.